Mice help scientists to understand the cancer genome

Yesterday I wrote about how studies carried out using genetically modified mice had enabled scientists to understand the role of the protein BLyS in the disease lupus, leading to the development of a new treatment, and last year I looked at how such studies were helping scientists to identify key genes that are involved in the development of heart disease. These are just two examples out of many of how studies in animals, particularly GM models, are helping scientists to understand the wealth of human genomic data that is becoming available, and a report on the website of Washington University in St. Louis provides another exciting example – the cancer genome.

A team at Washington University in St. Louis led by Professor Timothy Ley have compared the mutations present in the genomes of human cancer cells from patients with acute promyelocytic leukemia (APL), a subtype of the blood cancer acute myeloid leukemia, with those in the cancer cells of genetically modified mice, enabling them to identify two key genes in the development of cancer out of hundreds.

Professor Ley pointed out that this work also highlights the value of mouse models of cancer.

There’s been an ongoing debate for 15 years about whether mouse models of cancer are relevant to cancer that develops in people, by sequencing this genome, I think the answer is clear: this mouse model is remarkably similar to the human disease. This gives us a new way to use whole-genome sequencing to rapidly identify the most relevant mutations in human cancers.”

GM mouse models of cancer are becoming more popular with cancer researchers, as they replicate human cancer more faithfully than the more traditional in vitro and subcutaneous xenograft models of cancer, which while useful for the initial screening of drug candidates usually use immortal cancer cell lines whose biology can be very different to that of the cancer cells in patients  (though studies conducted by Professor Heinz-Herbert Fiebig of the Institute for Experimental Oncology in Freiburg show that xenograft studies that use cells taken directly from human tumors are much more accurate than those using standard cancer cell lines).

An example of this is provided by a report on how scientists at the Dana Farber Institute who have have shown that the malaria drug hydroxychloroquine slows pancreatic cancer growth in 3 mouse tumour models.

While hydroxychloroquine was highly effective against pancreatic cancer cell lines in vitro and when the cells were implanted subcutaneously in mice, it was less effective against the same cells when they were implanted into the pancreas of the mice – termed orthotopic transplants – and in a GM mouse model of pancreatic cancer. Nevertheless the activity of hydroxychloroquine against these more advanced mouse models of pancreatic cancer – a cancer for which treatment is currently very limited – was still substantial, and since this drug is already in widespread use against malaria it is an excellent candidate for accelerates transition to clinical trials in pancreatic cancer patients.

It’s a great example of thorough and thoughtful cancer research, and shows the importance of evaluating cancer drug candidates that appear effective against standard cell lines (in vitro or in subcutaneous mouse models) in more advanced animal models of cancer before starting clinical trials.

Addendum 25 March 2011: The University of Pennsylvania has a great article on its website discussing another exciting study that combines clinical research and a genetically modified mouse model of pancreatic cancer to develop new treatments for this disease.

Paul Browne